Since adjuvant radiotherapy was introduced in the 1970s for soft tissue sarcoma (STS), sequential clinical trials characterized the toxicities induced by radiotherapy when given post-operatively and pre-operatively. Gradual technological advancements led to more precise radiotherapy delivery through intensity-modulated radiation therapy (IMRT) and more accurate targeting through image-guided radiotherapy (IGRT) to minimize normal tissues from high-dose irradiation. These improvements ultimately reduced the long-term toxicities from radiotherapy. Due to the rarity and complexity of the disease, patients with STS should be treated at institutes where multidisciplinary discussion and care can be provided. Patients with STS should ideally be offered the choice of participating in clinical trials. International phase III trials are ongoing through COG-NRG Oncology (Pazopanib Neoadjuvant Trial in Non-Rhabdomyosarcoma Soft Tissue Sarcomas (PAZNTIS)) to define the role of radiotherapy in combination with pazopanib in the clinical care of extremity STS and through EORTC (STRASS) to define the role of pre-operative radiotherapy in the treatment of retroperitoneal STS. Outside of clinical trials, extremity STS should be treated at centers of expertise where high-quality IMRT-IGRT is administered to lessen acute and long-term toxicities. In patients with extremity STS, pre-operative IMRT-IGRT is preferred as better target delineation and image guidance can be achieved. While acute wound complication remains a concern, patients treated using pre-operative IMRT-IGRT are largely spared of severe chronic irreversible radiation-related side effects such as bone fracture, fibrosis, edema, and joint stiffness that alter limb functions. For STS originating from the retroperitoneum, if radiotherapy is recommended following multidisciplinary case discussion, pre-operative radiotherapy is preferred over post-operative radiotherapy. Post-operatively, normal radiosensitive organs fill the surgical cavity, which is the targeted volume of radiotherapy; hence, post-operative radiotherapy for retroperitoneal STS is associated with severe to fatal toxicities. Pre-operative radiotherapy has a more favorable toxicity profile as the retroperitoneal STS displaces, and thus spares, normal structures and organs from the high-dose irradiation volume.